A series of cortico-basal ganglia loops interconnect the cortex and basal ganglia by way of corticostriatal, striatopallidal, pallidothalamic and then finally thalamocortical circuits. We propose to examine such cortico- basal ganglia loops in three coordinated Aims. Diverse functions are thought to be represented by these different cortico-basal ganglia loops. Some are involved in sensory or perceptual function, others appear to subserve motor functions, and yet others seem to be related to cognition, emotion and affect. It is currently thought that the functional domain of each cortico-basal ganglia loop is established by the neocortical area from which the particular loop originates. In the proposed experiments, we will focus on two such loops. The first is a cortico-basal ganglia loop originating in the far anterior cingulate cortex. Evidence suggests that this loop is involved in conflict resolution and emotional control. The cortico-basal ganglia loop originating in this far anterior cingulate cortex (ACC) has been implicated in neuropsychiatric syndromes such as obsessive- compulsive disorder and depression. The second loop that we propose to study originates in the dorsolateral prefrontal cortex (DLPFC), which appears to be part of a frontal executive control system involved in selecting, planning, and timing sequential behaviors. The cortico-basal ganglia loop originating in the DLPFC has been implicated in a range of neurologic disorders including Parkinson's disease. Although such cortico-basal ganglia loops appear to be of enormous importance clinically, very little is yet known about how such individual cortico-basal ganglia loops function, and what precisely the basal ganglia contribute to loop functions. To approach this critical issue, we propose three Specific Aims focusing on studying the cortico-basal ganglia loops originating in the pregenual ACC and the DLPFC. We propose to use multi-electrode chronic recording methods in macaques to record spike activity and local field potential activity in the cortex and striatum simultaneously. The tasks proposed have been planned so that the subjects will perform either a task designed to activate the ACC or a task designed to activate the DLPFC. The ACC tasks involved approach-approach and approach-avoidance joystick tasks, and the DLPFC tasks involved simultaneously and sequentially cued sequential joystick movement tasks. By conducting parallel recordings in the cortex and striatum at sites designed to be in the ACC loop and the DLPFC loop, our goal is to determine neural mechanisms contributing to the function of these cortico-basal ganglia loops, through comparing cortical and striatal activity patterns within and across the loops. These experiments will be augmented by local inactivation and stimulation at the cortical origins of the loop. Our goal is to help to establish a therapeutically useful, mechanistic understanding of cortico-basal ganglia loop functions, and specifically the functions of two major cortico-basal ganglia loops whose dysfunction is strongly implicated in human neurologic and neuropsychiatric disorders. PUBLIC HEALTH RELEVANCE: The cortico-basal ganglia loops that we propose to study are implicated in a wide range of human neurologic and neuropsychiatric disorders, such as Parkinson's disease, Huntington's disease, Tourette syndrome, obsessive-compulsive disorder, addiction and depression. By carrying out studies to determine the function of these anatomically defined loops and the interactions among them in mediating behaviors, our study will contribute greatly to the understanding of neural bases of these disorders and to the development of treatment and cure of such diseases